Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Abstract

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The selfadministered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P ¼ 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P ¼ 0.07), time to PD (4.5 vs 2.2 months, P ¼ 0.13) and clinical benefit (CR þ PR þ SD) (58 vs 37%, P ¼ 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

“…The two studies had exactly the same clinical design and patient selection criteria. The outcome of the individual studies differed as the Danish study (n ¼ 63) showed a trend towards improved efficacy in favour of IL-2/HDC, whereas the UK study (n ¼ 41) was negative for all end points (Donskov et al, 2005). So, based on the randomised trials by themselves, no clear-cut effect of adding histamine to IL-2 was recognized.…”

“…A randomised phase II trial of IL-2 with and without HDC in mRCC was run independently in Manchester, UK in parallel with the present trial (Donskov et al, 2005). The two studies had exactly the same clinical design and patient selection criteria.…”

“…Thirty-three patients were randomly assigned to IL-2/HDC therapy and 30 to IL-2 alone. The clinical outcome of this and a parallel UK study has been published separately (Donskov et al, 2005). In summary, our Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P ¼ 0.03) and a trend towards an improved median survival time (18.3 vs 11.4 months, P ¼ 0.07) and an improved clinical benefit (CR þ PR þ SD) (58 vs 37%, P ¼ 0.10) in favour of IL-2/HDC compared with IL-2 alone.…”

“…Two randomised phase II trials of IL-2 with and without HDC were run in parallel, one in Aarhus, Denmark and one in Manchester, United Kingdom (Donskov et al, 2005). Only patients randomised in the Danish study were included in the blood and tumour study.…”

“…We have explored this potential mechanism clinically in a randomised phase II trial in metastatic renal cell carcinoma (mRCC) (Donskov et al, 2005). As a supplement to the clinical trial in Denmark, the present biological study was initiated to search for a potential histamine effect in situ.…”